The aggregation of amyloid-beta (Abeta) peptide and its deposition in parts of the brain and cerebral vasculature form the central processes in the etiology of Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA), respectively. Overwhelming evidence indicates low-molecular weight, soluble oligomers of Abeta (? 2 to 30mers) are the primary toxic agents inflicting synaptic dysfunction and eventually, neuronal death. However, how these toxic agents proliferate and induce widespread amyloid deposition throughout the brain, and what mechanism is involved in the amplification and propagation of toxic species are far from clear. Emerging evidence based on transgenic mice models suggest a transmissible nature of both endogenous and synthetic Abeta aggregates and implicate a prion-like mechanism of propagation in the dissemination and proliferation of toxic Abeta seeds. The pathogenic similarities between Abeta aggregates and mammalian prions do suggest that propagation may involve a conserved, template-assisted corruptive mechanism, by which specific oligomers gets replicated (and amplified) at the cost of fibril formation. Based on newly emerging data, it is increasingly being speculated that such prion-type transmissibility could be conserved across many amyloid diseases, but remains poorly understood. One of the main impediments for such an investigation has been the difficulty in isolating Abeta oligomers that are stable enough for biophysical analysis. Recently, we reported a self- propagating oligomer of Abeta42 (12-18mers) in vitro called Large Fatty Acid-derived Oligomers (LFAOs) (Kumar et al., 2012, J. Biol Chem), which is toxic to human neuroblastoma cells. Based on our preliminary data, we hypothesize that LFAOs are unique prion-like oligomers capable of cross-propagation by inducing 'corruptive propagation' to other homologous amyloidogenic proteins leading to biochemical similar toxic structures. In this project, we propose to use wild-type Abeta and specific CAA-linked mutant isoforms (Arctic, Dutch and Italian) to test our hypothesis and delineate fidelity of LFAO self-propagation (Aim 1) and the mechanism involved in cross-propagation (Aim 2), which form the basis for transmissibility. LFAOs, being the only biophysically well- characterized prion-like oligomers, present an ideal opportunity to investigate their molecular properties governing propagation. Mainly we will use in vitro biophysical methods to determine the mechanism and fidelity of propagation reactions, and to test how biophysical differences/similarities manifest in cellular functions by specific assays on both primary neuronal and primary endothelial cells. These investigations will lead to a profound understanding on the molecular aspects of transmissibility among Abeta aggregates, opening new perspectives in AD pathogenesis. In addition, this R15 proposal will provide significant inter-disciplinary research training opportunities for graduate and undergraduate students, which is an equally important objective of the proposed project.